Determining the precise lifespan of human T cells is challenging due to an inability to distinguish between dividing and dying cells. We were able to utilize and naturally occurring mutant of HIV-1 to follow the fate of a single cell over a 20-year period. This study demonstrated that effector memory T cells can live for more than 17-years as opposed to the several months currently noted in the literature. CD4+ (helper) T cell depletion is a hallmark of HIV infection. While in part explained by direct infection of the cells by HIV, it is likely that other mechanisms exist. By combining studies of human peripheral blood with murine models we were able to demonstrate that CD4 lymphopenia in the presence of persistent elevations in levels of type 1 interferon can lead to sustained and progressive CD4+ T cell lymphopenia. IL-27 is an immunomodulatory cytokine with potent anti-HIV properties in vitro. In a study design to assess the potential effects of this cytokine on HIV replication in vivo, plasma IL-27 levels were measured in 462 patients with HIV infection and 43 controls. No associations were seen between plasma levels of IL-27 and plasma levels of HIV-1.